Mucosal tissues represent the most common sites of infection. Establishing memory CD8 T cells at mucosal sites through vaccination may be critical for protecting the host against certain infections, including HIV. However, surprisingly little is known about the properties of memory CD8 T cells within the gastrointestinal and genital mucosa, the mechanisms that regulate their establishment, maintenance and differentiation state, and most importantly, what mucosal memory CD8 T cells within these tissues actually contribute to protection from local infections. These gaps in knowledge represent a major barrier to the successful development of protective CD8 T cell vaccines against mucosal pathogens. The main goal of this proposal is to use mouse models of infection to determine how protective CD8 T cell immunity is regulated at mucosal surfaces. To address this question, we will: 1) define mechanisms that regulate location-specific mucosal memory CD8 T cell differentiation states, 2) determine processes that govern CD8 T cell migration and maintenance within mucosal tissues, and 3) test the relationship between memory CD8 T cell location and differentiation state and the ability of the host to protect itself against intracellular pathogens encountered at mucosal surfaces. Specifically, we will test the hypothesis that establishing protective CD8 T cell immunity at mucosal portals of infection is controlled by three processes: developmental cues during priming within lymphoid tissues, the regulation of antigen-specific T cell trapping within mucosal parenchyma, and location specific cues that vary among different mucosal tissues and control memory T cell differentiation programs. Our studies may provide information for the design of vaccines that optimally establish protective CD8 T cell immunity at mucosal portals of infection.